|Year : 2017 | Volume
| Issue : 3 | Page : 99-105
Congenital hypothyroidism - An Indian perspective
Ambika G Unnikrishnan1, Upal Vyas2
1 Department of Endocrinology, Chellaram Diabetes Institute, Pune, India
2 Abbott Limited., Mumbai, Maharashtra, India
|Date of Web Publication||9-Oct-2017|
Ambika G Unnikrishnan
Department of Endocrinology, Chellaram Diabetes Institute, Pune - 411 021, Maharashtra
Source of Support: None, Conflict of Interest: None
Congenital hypothyroidism (CH) is a preventable cause of mental retardation in neonates. In India, CH is compounded by a lack of efficient newborn screening (NBS) programs, nonavailability of infrastructure, and the rising cost of health care. This review focuses on NBS techniques for early detection of CH, along with management strategies in the Indian scenario. Guidelines recommend measuring thyroid-stimulating hormone (TSH) or thyroxine (T4) levels or combined TSH and T4 as an ideal approach for screening CH within 2–4 days after birth. In preterm and low birth weight neonates, additionally, after 2–4 weeks, a follow-up screening has been suggested. If laboratory test is positive, a noninvasive scintigraphy and/or ultrasound has also been suggested as additional test to identify underlying etiology. Levo-T4 (L-T4) has been recommended as the first-line treatment with an initial standard dose of 10–15 μg/kg/day, based on the disease severity; with regular follow-up, up to 3 years of age. Although L-T4 tablet form is the standard of care in many developing countries like India, liquid formulations of L-T4 have been found to possess some additional beneficial effects. In summary, the government or policymakers should encourage mandatory cost-effective NBS for the early detection and treatment of CH.
Keywords: Congenital hypothyroidism, levothyroxine, newborn screening, thyroxine, thyroid-stimulating hormone
|How to cite this article:|
Unnikrishnan AG, Vyas U. Congenital hypothyroidism - An Indian perspective. Thyroid Res Pract 2017;14:99-105
| Introduction|| |
Congenital hypothyroidism (CH) is an important preventable cause of mental retardation. Since the clinical manifestations of CH are often subtle or absent at birth, many newborns remain undiagnosed and may later suffer from mental retardation.,, The inclusion of newborn screening (NBS) in India's public health policy is strongly advocated by the Indian Academy of Pediatrics (IAP). The current review focuses on various guidelines-driven screening and treatment modalities being used for the early CH detection and management in an Indian context.
| Epidemiology|| |
The overall incidence of CH ranges from 1:3000 to 1:4000 globally. Although the exact incidence of CH in India is unknown, a considerably older study conducted in 1998 reported the incidence to be 1:2640 of neonates among Indian neonates. The state-wise incidence reports 1:1985, 2.1:1000, 1.6:1000, 1:1700, and 1:1221 cases of CH in Hyderabad, Kochi, Chennai, Andhra Pradesh, and Uttar Pradesh, respectively.,,, Such a high incidence might be due to the advancement in screening methods as well as increased preterm birth rate. Another recent study conducted by the Indian Council of Medical Research (ICMR) which screened several inborn metabolic disorders between 2007 and 2012 in Delhi, Mumbai, Chennai, Hyderabad, and Kolkata reported the overall incidence of CH to be 1:1130 newborns.
| Classification|| |
CH has been classified into permanent CH (sustained deficiency of thyroid hormone warranting lifetime treatment), transient CH (temporary phase of thyroid hormone deficiency detected at the time of birth, which gets recovered to normal thyroid hormone levels), and syndromic hypothyroidism (where CH is associated with impairment of other organ systems). Permanent CH is usually further categorized into permanent, secondary/central, and transient primary CH.
| Etiology|| |
CH is majorly (80%–85%) caused due to nongenetic reasons, namely deficient thyroid embryogenesis leading to thyroid gland agenesis or dysgenesis. Fewer CH cases (10%) occur due to genetic reasons or inborn errors which include impaired thyroxine (T4) synthesis. The mutations in the transcription factors (PAX-8 and TTF-2) and in the genetic coding for sodium/iodide symporter, thyroid peroxidase, and thyroglobulin are also responsible for causing CH., Deficiency of maternal iodine is another common contributing factor resulting in CH consequently leading to abnormal fetal development. Consumption of optimum iodine supplements during pregnancy can prevent the occurrence of CH in neonates. However, transfer of excess of iodine to fetus through placenta or secretion of iodine in breast milk may also result in CH among neonates.,
| Need for Newborn Screening Program: Focus on the Indian Population|| |
In India, screening of newborn infants is complex due to difficulty in following up with the patient postdischarge for reconfirmation. A high proportion of home births adds to the challenge of successful NBS. A study conducted among urban Delhi population in 2014 reported 53% home births. While another study conducted in 2010 reported 14% home births in Nagpur and 16.3% in Belgaum. In addition, the attendants involved with home births were inadequately trained, lacked basic equipment, and did not have access to screening laboratories/medications., There are only a few screening programs and facilities due to high cost involved. Moreover, lack of reliable laboratories at large scale and unavailability of accurate Indian CH data are the other problems that contribute to fewer screening programs. A study conducted in 2001 reported that only 5%–10% children have been diagnosed with CH under a screening program in India. Therefore, India warrants an effective, robust, and cost-effective screening program.
The first Indian NBS program was conducted in Bangalore in 1980 for screening of various metabolic disorders responsible for mental retardation. Early detection and treatment of CH with the assistance of NBS program's may help improve outcomes in children and neonates. It has also decreased the burden of morbidity and mortality., Further, NBS for CH becomes additionally useful in neonates with nonthyroid congenital malformations, which are observed in about 8%–10% of the infants.,,
The NBS program includes filter paper card screening, follow-up of neonates with abnormal test results, and educating parents as well as the health-care providers. For early detection of birth defects, deficiencies, developmental delays, and disabilities, a NBS program, “Rashtriya Bal Swasthya Karyakram,” under the umbrella of National Rural Health Mission (NRHM) was launched by the Ministry of Health and Family Welfare.,
The ICMR which screened for inborn metabolic disorders (2007–2012) in neonates from Delhi, Mumbai, Chennai, Hyderabad, and Kolkata reported an overall incidence for CH of 1:1130 newborns. This study emphasized on the need for adequate infrastructure, space, and resources as a part of the NBS.
As many of the Indian states do not have government-funded screening programs, there is a need to encourage pediatricians and neonatologists to educate parents about the importance of screening for CH. The current challenges associated with implementing NBS include developing adequate infrastructure, employing appropriate diagnostic methods, and the rising costs associated with the endeavor. Furthermore, studies focusing on the outcomes of screening programs, in Indian context, are still lacking.
| Screening Methods|| |
The goal of neonatal screening is to detect all forms of primary and secondary CH with an emphasis on the severe forms of CH.
Screening of primary CH is recommended by measuring thyroid-stimulating hormone (TSH) in cord blood or blood collected after 24 h of age although the best “window” for testing is 48–72 h of age after normal term delivery., Second sampling is recommended at 2 weeks of life for premature, sick, or low birth weight (<1.5 kg) neonates. Furthermore, caregivers of neonates, discharged within 24 h of birth or in case of home delivery, are advised to visit hospital for sampling, within 1 week.,
In India, majority of the screening programs are conducted between 2nd and 5th day of birth, to minimize false-positive high values (unless placental or cord blood is used) due to the physiological neonatal surge in TSH (within 30 min of birth). In most screening programs, false positive to confirmed CH case ratio is 2–3:1. Further, reconfirmation is required in cases testing positive on first screening within 1–2 weeks of birth to correct errors that might have occurred during screening procedure. Moreover, during screening, irrespective of methodology used, nearly 5% of CH may be missed due to testing or data analysis inaccuracies, sample handling errors, or immaturity of the H-P axis with a delayed rise in TSH.
Various screening methods recommended in the guidelines of American Academy of Pediatrics (AAP), European Society for Pediatric Endocrinology (ESPE), and Australian Pediatric Endocrine Group (APEG) for detecting CH are described in [Table 1].
|Table 1: Advantages and disadvantages of congenital hypothyroidism screening methods|
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Primary thyroid-stimulating hormone
The primary screening test for the detection of CH is TSH measurement, which is the most sensitive test for detecting primary CH., According to AAP guidelines, neonates with serum TSH >40 mIU/L should be diagnosed for CH. In India, TSH cutoff values are >34 mIU/L during 24–48 h of life and >20 mIU/L after 48 h on repeat filter paper TSH and >40 mIU/L at any age. TSH-immunoradiometric assay (IRMA) kit with whole blood is used for TSH measurement in India. For detecting infants with delayed TSH rise, repeated screening after few weeks is recommended, especially in preterm births.
The primary T4 screening uses filter paper blood spot for measuring T4 levels, followed by TSH measurements in neonates with low or low normal T4.,
Combined thyroxine and thyroid-stimulating hormone
According to AAP guidelines, screening of combined TSH and T4 for detection of CH is ideal, particularly when free T4 (FT4) is measured accurately and cost effectively in elutes from filter paper blood spot., An increased TSH helps in diagnosing CH; however, it does not help in estimating its severity. In addition, T4 is a reliable parameter for estimating the severity of CH; however, it may create complexity in evaluating children with normal or low normal T4 values.
Screening in special category infants
A second or follow-up screening in ill and preterm neonates who have been admitted to the neonatal intensive care units and have a low or very low birth weight (VLBW) is recommended. In addition, multiples are also recommended for a second or follow-up screening. According to APEG guidelines for VLBW infants, TSH screening should be repeated after few weeks (2–4 weeks, depending on the weight) of initial screening because immaturity of the hypothalamic-pituitary-thyroid axis may initially mask primary CH.
Interpretation of screening test
Interpretations of screening results should be carefully performed to detect the different forms of CH, appropriate follow-up, and treatment strategies. The CH diagnosis is based on the thyroid function tests in newborns; the results are interpreted based on the values of T4 and TSH as described in [Table 2]. In general, a TSH ≥ 40 mIU/L on the 2–4 day of life warrants therapy, whereas values between 15 and 40 mIU/L may be carefully reassessed [Table 2].
|Table 2: Diagnostic Interpretation on the type of congenital hypothyroidism based on thyroid-stimulating hormone and thyroxine levels|
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To avoid growth abnormalities, parents of neonates with CH should be made aware of the importance of regular follow-up and adequate monitoring.,, At follow-up, factors such as thyroid function, improvement in clinical features, and changes in bone age should be evaluated. Frequency of follow-up as per different international guidelines is presented in [Table 3]. Since clinical differentiation between permanent and transient CH is not easy, a regular follow-up should be instituted up to 3 years of age. Moreover, levo-T4 (L-T4) treatment should be adjusted based on the type of CH., In India, infants assessed with borderline T4 or TSH values should be followed up biweekly or on monthly basis until both reach to normal levels.
| Management|| |
Treatment strategies and dosage
Many children with CH remain undetected and sustain mental retardation with moderate-to-severe learning difficulties, which could be a result of inadequate screening. Guidelines from international organizations recommend T4 as the first-line treatment for CH. Furthermore, as per ESPE guidelines, use of T4 in liquid formulations is only allowed if it is pharmaceutically produced. At present, in India, only oral/tablet form of L-T4 is used which is crushed and given with mother's feed, boiled cooled water, or formula milk.
Dose of thyroxine
International guidelines recommend that L-T4 treatment should be initiated as early as possible. According to ESPE guidelines, an initial dose of 10–15 μg/kg/day should be given. However, it may vary depending on the severity of CH.,, Similar dose is being used in India. Further clinical studies have reported that the dose and treatment initiation time point (now in terms of days and not as of months of life) are sensitive factors. Although treatment with L-T4 (10–15 μg/kg/day) increases serum T4 to >10 μg/dL in 7 days, TSH may take several months to suppress after treatment initiation. The age-related therapeutic doses of T4 are given in [Table 4]. As the therapeutic window of L-T4 is very narrow, the difference between under- and over-dosage is marginal.
|Table 4: Age-dependent therapeutic doses of thyroxine for congenital hypothyroidism|
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In spite of early diagnosis and treatment, many children exhibit developmental abnormalities due to age or delay in initiating L-T4 therapy, the parents' noncompliance to NBS program and L-T4 dosing, low initial dosage of L-T4, lack of adequate monitoring, underlying etiology, and/or socioeconomic factors.,,
Under- and over-treatment of congenital hypothyroidism
While undertreatment of CH is undesirable, a recent study has suggested a potential risk of overtreatment rather than undertreatment on the neurodevelopmental outcome in CH patients. Bongers-Schokking et al. assessed the cognitive development of 61 CH patients at 2, 6, and 11 years of age and correlated these results with severity of CH, time to TSH normalization, and episodes of over- and under-treatment as defined by either serum FT4 or TSH. Rapid normalization of TSH was associated with a higher mental development index at 2 years of age (by 13.3/100 points, P < 0.001). However, this difference was no longer evident by 11 years of age. Contrary to expectation, undertreatment of CH had no effect on cognitive outcome at any age, whereas overtreatment (defined by elevated FT4 levels) was associated with a significantly lower IQ at age 11 (P< 0.014). When overtreatment was defined based on TSH rather than FT4, no effect of overtreatment on cognitive development was observed. The authors suggested that FT4 may be a more sensitive marker of overtreatment than TSH, perhaps because of the relative pituitary resistance to TSH suppression observed in many CH patients' early in life. These data emphasize the importance of long-term follow-up when assessing cognitive outcome. Although they are provocative, the magnitude of the observed impairment seems quite large for the mild degree of FT4 elevation in overtreated patients, and these findings await validation in additional studies.
Preterm and LBW infants commonly manifest a pattern of low T4 and normal TSH termed “transient hypothyroxinemia of prematurity (THOP).” Although THOP has been associated with poor medical and neurodevelopmental outcomes, a causal relationship has not been established, and the few existing trials on treatment for THOP have not demonstrated a clear benefit. In this context, Scratch et al. attempted to correlate serum FT4 levels in 83 preterm infants (<30 weeks) with a wide range of neurodevelopmental outcomes at 7 years of age. Contrary to expectation, higher FT4 levels over the first 2 weeks of life were associated with poorer verbal learning (P< 0.02), verbal memory (P< 0.03), and slower reaction time (P< 0.001).
Mode of levothyroxine administration
According to AAP, ESPE, and APEG guidelines, T4 tablet is given to infants by crushing the required dose with few milliliters of breast milk/water in a single dose daily at a fixed time.,, The administration of L-T4 is recommended 30–60 min before breakfast to avoid interference of its absorption with food materials. Studies have shown that optimal absorption of L-T4 occurs while fasting, whereas its absorption is found to reduce by 40%–80% after food/drink intake. A study comparing morning versus bedtime administration of L-T4 reported lower serum TSH levels in fasting state than in nonfasting conditions, thereby confirming the findings.
Levothyroxine formulations – What is new?
The first Food and Drug Administration-approved L-T4 formulation was in tablet form. L-T4 in the market is present in both solid (tablets) and liquid formulations for oral use. It is suggested to provide L-T4 to children after mixing/dissolving crushed tablet with food/water to ensure intake of entire dose., To avoid over- or under-treatment, the dosage should be optimized properly with respect to age of infants and severity of CH., The dosage influences the time taken to achieve normal thyroid functions. If optimal dosage is given, the patients attain normal thyroid function quickly as compared to patients getting suboptimal dose. The New England CH Collaborative also highlighted the importance of adequate dosage treatment to maintain IQ among children. In recent times, a liquid formulation of L-T4 has been suggested by the research community., The liquid dosage can be individualized as per the age and severity of the disease, and its administration is encouraged over tablet formulations to minimize adverse effects due to over- or under-dosage. The liquid formulation is approved and available in France and the United Kingdom.
Previously conducted studies focusing on the initial dose and safety of different formulations of L-T4 have shown that both liquid and tablet formulations of L-T4 (10–15 μg/kg/day) normalized thyroid function within 7–10 days of administration.,, Furthermore, in neonates with moderate or severe CH, liquid L-T4 treatment was reported to be better in absorption compared to tablet formulation. Yue et al. demonstrated that L-T4 in liquid formulation peaks in blood faster than the tablet or the soft gel capsule (faster at maximum concentration (ng/mL) by an average of 30 min).
Exploring the positive aspects of liquid formulations, Von Heppe et al. reported that liquid formulation was easier to handle and enabled parents to individualize the dosage as per the severity of disease; the dosage could be modified as per age and severity of CH, which attempts to minimize adverse effects due to over- or under-dosage., Furthermore, a survey has suggested that parents of children with CH preferred the liquid formulation of L-T4. However, to the best of our knowledge, there are no studies from India, assessing the efficacy and safety of liquid formulation of L-T4 in CH treatment. Further research is required to ascertain the benefits of L-T4 liquid formulation in an Indian setting.
| Debates and Uncertain Areas|| |
Studies suggest a high incidence of CH in India. This could be due to the implementation of standardized, nation-wide NBS programs, delay in TSH rise (missed at the time of first NBS), and variations in the diagnostic criteria (lowering of screening test cutoff values)., Diagnostic delays, delay in CH treatment, and irregularities in the management of CH (due to inadequate treatment, poor adherence to regimen, lack of monitoring, under- or over-dosage of treatment drug) can result in impaired neurocognitive outcome. Thus, to avoid growth and developmental complications later in their life, improvements in the NBS program are needed to identify and treat CH. An appropriate and adequate initial therapy and follow-up are essential in CH.,
| Conclusions|| |
Timely diagnosis and appropriate treatment of CH is important to improve CH-related outcomes. Primary screening should be carried out by TSH testing with regular follow-up. As stringent routine screening is not followed in India, awareness among health-care practitioners and parents regarding the importance of early diagnosis and initiation of therapy is warranted. In addition, government or policymakers should encourage mandatory cost-effective screening programs for early detection and treatment of CH. This is also strongly recommended by IAP.
Treatment options available for CH include tablet and liquid L-T4 formulations. L-T4 in tablet form is the recommended standard of care, with literature supporting the same. Emerging evidences suggest that in future, a pharmaceutically manufactured formulation of L-T4 in solution form, in the appropriate dosage, could be used for the treatment of CH.
The authors would like to acknowledge Turacoz Healthcare Solutions (http://www.turacoz.com” www.turacoz.com) for providing end-to-end publication support.
Financial support and sponsorship
Conflicts of interest
Dr Unnikrishnan AG has been an investigator/author in reports of studies conducted by Abbott India Ltd as well as other pharmaceutical companies. Dr. Upal Vyas is an employee of Abbott India Ltd. All authors have indicated that they have no other conflicts of interest regarding the content of this article.
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[Table 1], [Table 2], [Table 3], [Table 4]